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Open Access Highly Accessed Research article

TRAIL and proteasome inhibitors combination induces a robust apoptosis in human malignant pleural mesothelioma cells through Mcl-1 and Akt protein cleavages

Bao-Zhu Yuan124*, Joshua Chapman2, Min Ding2, Junzhi Wang1, Binghua Jiang3, Yon Rojanasakul3 and Steven H Reynolds2

Author Affiliations

1 National Institutes for Food and Drug Control, Beijing, 100050, China

2 National Institute for Occupational Safety and Health, CDC, Morgantown, WV, 26505, USA

3 Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV, 26506, USA

4 Department of Cell Biology, National Institute for Food and Drug Control, 2 Tiantan Xili, Dongcheng District, Beijing, 100038, China

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BMC Cancer 2013, 13:140  doi:10.1186/1471-2407-13-140

Published: 22 March 2013

Abstract

Background

Malignant pleural mesothelioma (MPM) is an aggressive malignancy closely associated with asbestos exposure and extremely resistant to current treatments. It exhibits a steady increase in incidence, thus necessitating an urgent development of effective new treatments.

Methods

Proteasome inhibitors (PIs) and TNFα-Related Apoptosis Inducing Ligand (TRAIL), have emerged as promising new anti-MPM agents. To develop effective new treatments, the proapoptotic effects of PIs, MG132 or Bortezomib, and TRAIL were investigated in MPM cell lines NCI-H2052, NCI-H2452 and NCI-H28, which represent three major histological types of human MPM.

Results

Treatment with 0.5-1 μM MG132 alone or 30 ng/mL Bortezomib alone induced a limited apoptosis in MPM cells associated with the elevated Mcl-1 protein level and hyperactive PI3K/Akt signaling. However, whereas 10–20 ng/ml TRAIL alone induced a limited apoptosis as well, TRAIL and PI combination triggered a robust apoptosis in all three MPM cell lines. The robust proapoptotic activity was found to be the consequence of a positive feedback mechanism-governed amplification of caspase activation and cleavage of both Mcl-1 and Akt proteins, and exhibited a relative selectivity in MPM cells than in non-tumorigenic Met-5A mesothelial cells.

Conclusion

The combinatorial treatment using TRAIL and PI may represent an effective new treatment for MPMs.

Keywords:
Malignant pleural mesothelioma; Apoptosis; Trail; Proteasome inhibitor; Mcl-1; Akt